(746.5) Genomic Rearrangement in Non-coding Region of Chromosome 1 Leads to Spontaneous Obesity and Heart Failure with Preserved Ejection Fraction

Poster Board Number: E374

Donnell White, III (Louisiana State University Health Sciences Center - New Orleans), Jian Wu (Louisiana State University Health Sciences Center - New Orleans), Lothar Lauterboeck (Louisiana State University Health Sciences Center - New Orleans), Robert Kesterson (University of Alabama at Birmingham), Qinglin Yang (Louisiana State University Health Sciences Center - New Orleans)

Background:

Obesity is a global epidemic leading to shorter life expectancies for the first time in recent U.S. history, and epidemiological studies predict that half of the U.S. adult population will be obese by 2030. Obesity is the most common comorbidity and risk factor for heart failure (HF) in patients with preserved ejection fraction (HFpEF), a subclass containing more than 50% of HF cases. However, effective treatment of HFpEF remains scarce due to the incomplete understanding of the mechanisms. Our lab discovered a spontaneously obese mouse line, with a genomic rearrangement in a non-coding region of chromosome 1. Most monogenic obesity animal models exploit the hypothalamic leptin–melanocortin feeding pathway. However, monogenic models are not representative of most human metabolic disease. This obesity animal model may better represent the numerous contributing mechanisms of obesity in humans, allowing us to find better solutions to help prevent further decline of health outcomes in the US.

Methods:

A mouse line (C57/B6J) of Floxed-stop Overexpression of IF1 (FEI) was generated and maintained for Cre-mediated conditional IF1 overexpression. We observed that severe obesity became a fixed phenotype in inbred FEI mice after inbreeding for 5-6 generations. Targeted-Locus-Amplification (TLA) analyses revealed that FEI inbreeding triggered a genomic rearrangement in a non-coding region of chromosome 1. In the present study, we focus on assessing the metabolic and cardiac phenotype of FEI mice using echocardiography, histology, glucose and insulin tolerance assays, and exercise tolerance tests.

Results:

Early onset obesity was consistent in FEI mice with increased peripheral fats and circulating tissue lipids, as well as reduced systemic metabolic rates. FEI mice also exhibited increased food intake, fasting blood glucose, insulin, and leptin with impaired glucose and insulin tolerance as early as 6 weeks of age. Echocardiography revealed that the FEI mice developed concentric left ventricular hypertrophy with preserved ejection fraction. However, E/A ratio results from Doppler flow measurement at mitral valve suggest diastolic dysfunction in the FEI mice. Heart weight:tibial length was increased in FEI compared to WT. Hamp;E and Trichrome blue staining on heart sections exhibited increased cardiomyocyte hypertrophy and cardiac fibrosis. Hamp;E of adipose tissue and liver revealed increased adipocyte size, and increased fat deposition, respectively. FEI exhibited significantly decreased exercise tolerance compared to WT.

Conclusions:

We conclude that the metabolic and cardiac phenotypes in the FEI mice closely recapitulate obese patients who suffer from HFpEF. Further studies on these mice should yield novel and translational insight into the genetic and metabolic mechanisms underlying the development of obesity and HFpEF, improving patient treatments.

This research was funded by ADA basic science Award (#1-17-IBS-184) to Q. Y. and NIH R01 HL135336 to Q.Y.